We propose a consortium of highly experienced transplant centers with an established track record of productive collaborations through the Cancer and Leukemia Group B (CALGB) Transplant Committee for the purposes of proposing, developing, and conducting innovative clinical trials within the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The clinical trial concept our consortium proposes focuses on reducing the alarmingly high risk of relapse observed in patients with recurrent diffuse large B-cell lymphoma (DLCL) following autologous hematopoietic cell transplantation (AHCT). DLCL remains the second most common indication for AHCT worldwide because many patients still relapse following chemotherapy and rituximab and may benefit from high dose chemotherapy. Nonetheless, the risk of relapse even after AHCT is too high, particularly for those who relapse within a year of completing therapy, and efforts to mitigate the risk of relapse following AHCT are essential. The immunomodulatory agent lenalidomide is currently being tested against a number of different subtypes of non-Hodgkins lymphoma (NHL) and has significant single agent activity in DLCL, even in those relapsing following AHCT. Another novel compound, PCI-32765 is a first-in-class selective inhibitor of Bruton's Tyrosine Kinase (BTK) which in a phase 1 study led to responses in 38% of patients with relapsed/refractory DLCL. Both agents have activity against the major molecular subtypes of DLCL, the germinal center B-cell like (GCB) and activated B-cell like (ABC). Relapsed DLCL patients are more likely to have the ABC subtype so there is a good rationale for targeting such patients with these agents. We hypothesize that as maintenance agents following AHCT, these compounds will decrease the risk of DLCL progression, particularly in patients with the ABC subtype. We will test this hypothesis with the following specific aims: Aim 1: We will perform a randomized Phase II study of high dose chemotherapy and AHCT followed by maintenance treatment with either lenalidomide or PCI-32765 in patients with DLCL at high risk for relapse following AHCT, using progression free survival at 2 years as the primary endpoint. Aim 2: We will explore the relationship between molecular subtypes of DLCL (GCB or ABC), determined by IHC staining of diagnostic DLCL biopsies, and patient outcomes following AHCT and maintenance treatment with either lenalidomide or PCI-32765. RELEVANCE (See instructions): Diffuse large B-cell lymphoma (DLCL) is the most common type of non-Hodgkin lymphoma. Many patients can be cured with current therapy but still too many patients relapse. When DLCL relapses, high dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) is the treatment of choice, but many patients relapse even after AHCT. We seek to test new agents following AHCT in patients with DLCL to determine if we can lower the risk of relapse and improve the lives of these patients.